Chordoma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2];Associate Editor(s)-in-Chief: Suveenkrishna Pothuru, M.B,B.S. [3]

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Synonyms and keywords: Notochordoma; Chordocarcinoma; Chordoepithelioma; Clival chordoma; Familial chordoma; Intracranial chordoma; Sacrococcygeal chordoma; Skull base chordoma; Skull-base chordoma; Spinal chordoma; Chondroid chordoma; Classical chordoma; Dedifferentiated chordoma

Overview

Chordoma is a rare bone cancer that is diagnosed in only about 300 patients in the U.S. each year. Chordoma accounts for 1% of intracranial tumors and 4% of all primary bone tumors. It occurs exclusively in the axial skeleton and has a predilection for the sacrum (50%), base of the skull (35%), and mobile spine (15%). The cells that give rise to arise from the notochord. The notochord is an important structure in the early embryonic life that degenerates before birth. However, even after birth, some cells from the notochord remain in bones at the base of the skull, vertebrae, and the coccyx. Rarely, one of these cells, which are called notochord remnants, undergoes changes that give rise to a chordoma. Since chordomas arise in bone, they are usually extradural and result in local bone destruction. On gross pathology, gelatinous mucoid substance, necrosis, hemorrhage, and calcification are characteristic findings of chordoma. On microscopic histopathological analysis, vacuolated cells with eccentric nucleus, physaliphorous cells, cytological atypia, and high mucin content within cytoplasm are characteristic findings of chordoma. Symptoms of chordoma include radicular pain and sensory deficit related to nerve root compression. Clival chordoma must be differentiated from chondrosarcoma of skull base, plasmacytoma, meningioma of skull base, pituitary macroadenoma, and ecchordosis physaliphora. Vertebral Chordoma must be differentiated from chondrosarcoma, giant cell tumor of bone, spinal metastases, plasmacytoma, and spinal lymphoma. The incidence of chordoma is approximately 0.1 per 100,000 individuals in the United States. Chordomas may appear at any age, but are most commonly noticed among patients older than 30 years of age. Men are more commonly affected with chordomas than females. Chordoma does not usually spread to other bones but can recur after treatment. Prognosis is generally poor, and the 10-year survival rate of patients with chordoma is approximately 40%. CT scan may be diagnostic of chordoma. Findings on CT scan suggestive of chordoma include expansile soft-tissue mass with a centrally located well-circumscribed destructive lytic lesion, marginal sclerosis, and irregular intratumoral calcifications. On MRI, chordoma is characterized by calcifications and bony expansion. Chemotherapy for chordomas usually results in low response rates. The predominant therapy for chordoma is surgical resection. Adjunctive radiation may be required.

Classification

Chordoma may be classified into three subtypes based on the tumors location along the spine: sacrococcygeal lesions, skull-base lesions, and vertebral body lesions . Chordomas are relatively evenly distributed among three locations:

Sacrococcygeal

This is the most common location, accounting for approximately 30-50% of all chordomas and involving particularly the fourth and fifth sacral segments. The tumor may be particularly large at presentation.

Skull-base

The clival region is the next most common, accounting for 30-35% of cases. Typically the mass projects in the midline posteriorly indenting the pons. This characteristic appearance has been termed the "thumb sign".

Vertebral Bodies

Chordomas of the vertebral bodies are rare but after lymphoproliferative tumors are nonetheless the most common primary malignancy of the spine in adults. Chordomas most commonly involve the cervical spine (particularly C2), followed by the lumbar spine then the thoracic spine. They often extend across the intervertebral disc space, involving more than one vertebral segment. Chordomas may extend into the epidural space, compressing the spinal cord, or along the nerve roots, enlarging the neural exit foramen.

Pathophysiology

On gross pathology, gelatinous mucoid substance, necrosis, hemorrhage, and calcification are characteristic findings of chordoma. On microscopic histopathological analysis, vacuolated cells with eccentric nucleus, physaliphorous cells, cytological atypia, and high mucin content within cytoplasm are characteristic findings of chordoma.

Gross Pathology

• On gross examination, chordomas are generally soft and appear to be well encapsulated.
• Lobulations are apparent on cut section, and the tumor usually has a bluish gray color with extensive gelatinous translucent areas that are focally cystic and hemorrhagic.
• In some patients, calcification and sequestered bone fragments are found as well.

Microscopic Pathology

• Cells are often vacuolated, displacing the nucleus eccentrically.
• Physaliphorous cells may be present.
• Cytological atypia may be present.
• High mucin content within cytoplasm and in matrix renders a deep, eosinophilic appearance on H&E stained sections.
• Characterized immunohistochemically by S-100 and epithelial membrane antigen positivity.
• Histologically, chordomas are categorized as classical (or conventional), chondroid, and dedifferentiated chordomas.
• Physaliphorous cells are typical of classical chordomas, appearing as groups of gray-white large cells separated by fibrous septa into lobules and surrounded by a basophilic extracellular matrix rich in mucin and glycogen.
• Chondroid chordomas show histological features resembling both chordoma and chondrosarcoma, a malignant tumor of the bone and soft tissue.
• Chondroid chordomas account for 5%–15% of all chordomas and up to 33% of all cranial chordomas, being preferentially found on the spheno-occipital side of the skull base.
• Despite an appearance that resembles hyaline cartilage, these tumors retain an epithelial phenotype and express specific chordoma markers, including cytokeratin and S-100, which are not found in cartilaginous tissue; this has suggested their alternative, more appropriate classification as “hyalinized chordomas”.
• Dedifferentiated chordomas are also rare, 10% of chordomas, and characterized by sarcomatous regions that are comprised of spindle-shaped polygonal cells.

• 

  Micrograph showing a chordoma. HPS stain.

• 

  Low power view. Somewhat lobulated tumor with loose areas, cellular areas, and fibrous septa.

• 

  Physaliphorous cells.

Genetics

• Recent genetic analysis of chordoma using high-resolution array comparative genomic hybridization among patients with familial chordoma revealed unique duplications in the 6q27 chromosomal region.
• Interestingly, the duplicated region only contained the T (brachyury) gene, which was previously found to be uniquely overexpressed in almost all sporadic chordomas compared with other bone or cartilaginous lesions.
• Brachyury regulates several compelling stem cell genes and has recently been implicated in promoting epithelial-mesenchymal transition in other human carcinomas.
• Although it is still not clear what role brachyury plays in the pathogenesis of chordomas, the identification of the duplication and the remarkable overexpression seen in samples suggest that it may be a critical molecular driver in the initiation and propagation of chordoma.

Differentiating Chordoma from other Diseases

Clival chordoma must be differentiated from other diseases such as:

• Chondrosarcoma of skull base
• Plasmacytoma
• Meningioma of skull base
• Pituitary macroadenoma
• Ecchordosis physaliphora

Vertebral chordoma must be differentiated from other diseases such as:

• Chondrosarcoma
  • Neural arch > vertebral body
  • Thoracic spine is the most commonly involved spinal region
  • Chondroid matrix (rings & arcs)
  • Similar MRI appearance to chordomas (low to intermediate signal intensity on T1, hyperintense on T2, enhances)

• Giant cell tumor of bone
  • Location: sacrum > thoracic spine > cervical spine > lumbar spine
  • No mineralised matrix
  • Heterogeneous intermediate to hyperintense T2 signal

• Spinal metastases
  • Hypointense on T1; variably hyperintense on T2
  • Often multiple, involving vertebral bodies and posterior elements

• Plasmacytoma
  • Destructive vertebral body lesion (similar appearance to lytic metastases)

• Spinal lymphoma
  • Multifocal disease
  • Heterogenous T2 signal

Epidemiology and Demographics

Chordomas are rare tumors that affect approximately one in a million individuals. Chordoma represents up to 4% of primary malignant bone tumors and 20% of primary spine tumors.

Incidence

• The incidence of chordoma is approximately 0.1 per 100,000 individuals in the United States.

Age

• Chordomas may appear at any age, but are most commonly noticed among patients older than 30 years of age.
• The median age at presentation for cranial chordomas is in the sixth decade, slightly younger for sacral chordomas, and with rare occurrences in the pediatric population.
• Chordomas in children and adolescents account for <5% of all chordoma cases.

Gender

• Males are more commonly affected with chordomas than females.

Natural History, Complications, Prognosis

Prognosis

• Prognosis is generally poor, and the 10-year survival rate of patients with chordoma is approximately 40%.
• The median survival of cranial base chordomas is estimated at 6.29 years, with 5-year overall survival and progression-free survival rates of 78.4% and 50.8%, respectively.
• The lethality of skull-base chordoma is largely due to local progression, although systemic metastasis has been reported in 12.5% of skull base tumors.

Complications

• Chordoma does not usually spread to other bones but can recur after treatment.
• Metastatic spread of chordoma is observed in 7-14% of patients and includes nodal, pulmonary, bone, cerebral or abdominal visceral involvement, predominantly from massive tumors.
• Incomplete delineation of the tumor and microscopic distal extension of tumor cells may explain the frequency of recurrences.

History and Symptoms

History

When evaluating a patient for chordoma, you should take a detailed history of the presenting symptom (duration, onset, progression), other associated symptoms, and a thorough past medical history review. Other specific areas of focus when obtaining the history are:

• Obtain a history of any previous treatment for degenerative disc disease or coccydynia.
• Obtain a history of any bowel, bladder, and sexual function.

Symptoms

The indolent and slow-growing features that commonly characterize chordomas contribute to their frequently asymptomatic clinical presentation. When patients present with symptoms, they usually have radicular pain and sensory deficit related to nerve root compression. The specific clinical presentation of chordoma is determined by the exact anatomical location of the tumor:

Symptoms observed in skull-base chordoma include:

• Double vision
• Headache
• Facial pain
• Swallowing difficulties

Symptoms observed in cervical spine chordoma include:

• Neck pain
• Hoarseness
• Dysphagia
• Laryngeal bleeding

Symptoms observed in sacral chordoma include:

• Vague low back pain
• Lower extremity radiculopathy
• Palpable mass
• Bowel and bladder dysfunction (from local organ mass effect)

Diagnosis

X Ray

• On X ray, chordoma appears as a solitary midline lesion with bony destruction.

CT

CT scan may be diagnostic of chordoma. Findings on CT scan suggestive of chordoma include:

• Expansile soft-tissue mass that usually hyper-attenuating relative to the adjacent brain.
• Centrally located well-circumscribed destructive lytic lesion
• Marginal sclerosis
• Nonhomogenous areas may be observed due to the presence of cystic necrosis or hemorrhage.
• The soft-tissue mass is often disproportionately large relative to the bony destruction.
• Irregular intratumoral calcifications (thought to represent sequestration of normal bone rather than dystrophic calcifications)
• Moderate to marked contrast enhancement

MRI

On MRI, chordoma is characterized by calcifications and bony expansion. MRI image characteristics observed among chordoma patients include:

• T1 weighted image:
  • Intermediate to low signal intensity
  • Small foci of hyperintensity (intratumoral hemorrhage or a mucus pool)

• 

  Chordoma Axial T1

• 

  Clival chordoma sagittal T1

• T2 weighted image:
  • Most exhibit very high signal

• 

  Clival chordoma Axial T2

• 

  Clival chordoma coronal T2

• T1 weighted image with gadolinium contrast:
  • Heterogeneous enhancement with a honeycomb appearance corresponding to low T1 signal areas within the tumor
  • Gradient echo confirms hemorrhage if present with blooming

Treatment

The predominant therapy for chordoma is surgical resection. Adjunctive radiation may be required.

Medical Therapy

Chemotherapy

• Chemotherapy for chordomas usually results in low response rates.
• Only a few clinical series have reported the use of chemotherapy for managing chordoma, which is generally used in the later course of the disease and only as palliative treatment.

Radiotherapy

• The use of radiotherapy as a primary or adjuvant treatment in various treatment paradigms for chordoma has been a subject of intense debate.
• Unfortunately, stand-alone radiotherapy has been ineffective, even when coupled with debulking or palliative decompression.
• The proximity of chordomas to vital neurological structures such as the brain stem and nerves limits the dose of radiation that can safely be delivered.
• Therefore, highly focused radiation such as proton therapy and carbon ion therapy are more effective than conventional x-ray radiation.
• Adjuvant proton beam therapy (PBT) after gross total resection is currently the accepted treatment standard in the management of chordoma, and it is the strategy currently favored by the authors.

Surgery

• The principal goals of surgery include:
  • Histologic confirmation of the lesion
  • Achieve a maximal safe resection
  • Provide symptomatic improvement
  • Facilitate adjuvant treatment such as radiotherapy, by minimizing the treatment volume and maximizing the distance between the target volume and critical surrounding neurovascular structures.
• Wide en bloc resection with adequate bone and soft tissue margins is the primary surgical goal.
• However, sometimes, wide margins are very difficult to attain because these tumors are located at sites that are difficult to access, with high rates of complications and sequelae.

References

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